The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with head injury underscores the need for improved therapeutic modalities. TBI in humans is a heterogeneous condition that differs substantially in severity, location, etiology, clinical presentation and neuropathology. This differs from experimental TBI studies where multiple variables are carefully controlled. The acute and chronic molecular, cellular, biochemical and pathophysiological events that follow TBI are complex and multi-factorial. There may not be a single "magic bullet" drug that will be completely successful in preventing secondary damage following brain injury. Rather, combinatorial drug treatments that target specific windows of secondary pathology may be more efficacious than treatment with a single drug. In the proposed experiments, the PIs will evaluate cellular and functional outcomes following TBI and administration of Cyclosporin A (CsA), followed by dietary choline supplementation. The combination of CsA and choline was chosen based on the clinical utility of these drugs, previously published work, and preliminary data generated by the Pauly/Scheff/Sullivan labs. The overall hypothesis of this proposal is that a combinatorial approach will optimize outcome compared to single or dual treatment modalities. The experiments will advance the understanding of the neurobiological consequences of TBI and determine the efficacy of a combined pharmacological/behavioral approach to recovery in two different models of brain injury. The outcome measures proposed will provide important new information about neurobiological outcomes following TBI. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. The studies proposed for this research are highly significant and could add to our understanding of the pathophysiology and therapeutic treatment of individuals with traumatic brain injuries. If the studies show benefit of combining CsA and choline, the PIs will meet with clinical investigators to see if this could possibly be a new trial or an add-on to the CsA trial under consideration for funding. Although the pharmacological experiments proposed are not particularly mechanistic, they are feasible and directly translatable into human patients. The NIH road map contends that if therapeutics are directly translatable to humans, mechanistic studies are not the initial priority. Two different models of rat TBI will be used in these experiments, the cortical contusion model of focal injury, and the medial fluid percussion model of diffuse injury. The combined outcome measure the PIs will test may provide better characterization of recovery than previously used in either the CCI or MFPI model. Finally, functional recovery in terms of cognition is a major focus of this grant. These studies are translational since both cyclosporin and choline are both approved for use in human patients. However, the animal literature has gaps, especially for the effects of CsA on cognitive recovery. Choline is readily available and could be administered to TBI patients outside of a critical care setting. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. PUBLIC HEALTH RELEVANCE: The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with traumatic brain injury (TBI) underscores the need for improved therapeutic modalities. The overall hypothesis of this proposal is that a combinatorial approach with cyclosporin A (CsA) and dietary choline supplementation will optimize outcome compared to single treatment modalities. CsA and choline are both approved by the FDA and actively being pursued in NIH-sponsored trials as monotherapy for human TBI patients. The PIs'hypothesis will be evaluated in two different models of rat TBI that have different mechanisms and timing of neuropathology. These studies are a logical extension of current trials in TBI, and will use a set of testable hypotheses to provide clinically relevant information about this drug combination.